Polyacrylic Acid/Calcium Phosphate Nanoparticles Blocking Autophagy for Enhanced Transarterial Chemoembolization Therapy of Hepatocellular Carcinoma

Transarterial chemoembolization (TACE) is commonly used for treating advanced hepatocellular carcinoma (HCC). However, the instability of lipiodol-drug emulsion and the altered tumor microenvironment (TME, such as hypoxia-induced autophagy) post-embolization are responsible for the unsatisfactory therapeutic outcomes. Herein, pH-responsive polyacrylic acid/calcium phosphate nanoparticles (PAA/CaP NPs) were synthesized and used as the carrier of epirubicin (EPI) to enhance the efficacy of TACE therapy through autophagy inhibition. PAA/CaP NPs have a high loading capacity of EPI and a sensitive drug release behavior under the acidic condition. Moreover, PAA/CaP NPs block autophagy through the dramatic increase of intracellular Ca2+ content, which synergistically enhances the toxicity of EPI. TACE with EPI-loaded PAA/CaP NPs dispersed in lipiodol shows obvious enhanced therapeutic outcome compared to the treatment with EPI-lipiodol emulsion in an orthotopic rabbit liver cancer model. This study not only develops a new delivery system for TACE but also provides a promising strategy targeting autophagy inhibition to improve the therapeutic effect of TACE for the HCC treatment.Funding Information: This work was supported by the Science and Technology Development Fund, Macau SAR (File no. 0168/2019/A3, SKL-QRCM(MUST)-2020-2022). Angiography and interventional studies were supported by the Department of Interventional Radiology at the Affiliated Hospital of Traditional Chinese Medicine of Southwest Medical University.Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.Ethical Approval: The animal study was approved by the Committee of Animal Protection and Use Institutions of Southwest Medical University (IACUC No.: SWMU20210409). The handing procedures were performed on the basis of the National Institutes of Health guide for the care and use of laboratory animals.